Psoriasis a chronic relapsing disease of the skin characterized by variable clinical features. The lesions are classified as erythrosquamous, which indicates that both the vasculature (erythema) and the epidermis (increased scale formation) are involved. Pustular psoriasis a variant of psoriasis with sterile pustules presenting locally or broadly on the skin either acutely, subacutely, or chronically (Camp, RDR (1998) Pustular forms of psoriasis. Textbook of Dermatology, Champion, R H et al eds, Blackwell Science, Oxford; 1633-43). Pustular psoriasis is frequently categorized as either generalized pustular psoriasis (GPP) or localized pustular psoriasis (Farber and Nall (1993) Cutis 51:29-32). In generalized pustular psoriasis, sterile pustules can cover almost the entire body, and in the localized form, pustules are confined to isolated locations. GPP includes von Zumbusch (acute GPP), generalized form of acrodermatitis continua (Hallopeau), acute exanthematic, GPP of pregnancy (impetigo herpetiformis), infantile and juvenile GPP, and circinate and annular GPP, whilst localized pustular psoriasis includes chronic and acute palmoplantar pustulosis. (Farber and Nall, supra; Iizuka et al (2003) Arch Dermatol Res 295:S55-S59).
GPP is a rare form of psoriasis that usually presents as numerous aseptic pustules occurring on reddened skin over the whole body and is a potentially life-threatening systemic inflammatory disease. It is frequently associated with fever, and involves the formation of subcorneal pustules histopathologically characterized by Kogoj's spongiform pustules. It is characterized by recurrence in periodic episodes. In the course of the disease, GPP patients may have laboratory abnormalities associated with systemic inflammation response, frequently complicated with mucosal symptoms and arthritis, and less frequently with respiratory failure, eye disease, or secondary amyloidosis. GPP can be preceded by psoriasis vulgaris (PV). However, this not always the case, and recent research shows that GPP that is not preceeded by PV is a distinct subtype of GPP, distinguishable from GPP with PV by a deficiency in the Interleukin 36 Receptor Antagonist (DITRA) due to mutations in IL36RN. (Sugiura et al. (2013) J. Investi. Derm. Accepted article preview 22 May 2013 (doi:10.1038/jid.2013.230)).
A “pustular psoriasis (generalized type) clinical practice guideline” has been published by the Japanese Dermatological Association (Iwatsuki K, Terui M, Ozawa A, et al. (2010) Clinical Guidelines for Generalized Pustular Psoriasis: Therapeutic Guides Incorporating Tumor Necrosis Factor-alpha Inhibitors), presenting information about the diagnosis and the severity criteria of GPP and recommending therapeutic guides for GPP, as an outcome of a “surveillance study on a rare intractable skin disorder” of the Japan Ministry of Health Labor Welfare (MHLW) Intractable Disease Conquest Research Program. In the guideline, systemic corticosteroids, ciclosporin, etretinate, methotrexate (MTX), and infliximab are recommended as the treatment for GPP. Infliximab, and other biologic drugs targeting TNF-α, have shown some treatment success (see, e.g., Viguier et al. (2012) Arch Dermatol 148:1423-25), as has ustekinumab (see, e.g., Dauden (2010) Br. J. Derm. 163:1346-68). However, only three drugs (ciclosporin, etretinate, and infliximab) are approved for use in the treatment of pustular psoriasis, and these drugs all have significant limitations. For example, systemic long-term corticosteroids cause Cushing's syndrome and hypertension, amongst other side effects. Methotrexate has well-known liver and hematology toxicity. Ciclosporin may be restricted due to its nephrotoxicity after chronic administration. Etretinate has a very long half-life (about 100 days) and is associated with teratogenicity. Moreover, the oral cavity symptom (including dryness of the mucosa) caused by etretinate often prevents the continuation of its treatment. For infliximab, it is reported that there is loss of response due to the development of neutralizing antibodies (Asahina A (2012) Biologics. Diagnosis, Understanding and Treatment Dermatology Clinical Asset 10 Current Understanding of the Pathology and Treatment of Psoriasis; Tokyo: Nakayamashoten, 264-8), and TNF alpha antagonists have the potential to reactivate tuberculosis.
There are fewer therapeutic options available for GPP than for plaque psoriasis, and those that are available have significant limitations. Hence, broadening the options for the treatment of GPP would address a high unmet medical need.